Prognostic relevance of Exercise Pulmonary Hypertension: Results of the multi-center PEX-NET Clinical Research Collaboration

Gabor Kovacs; Marc Humbert; Alexander Avian; Gregory D Lewis; Silvia Ulrich; Anton Vonk Noordegraaf; Rogerio Souza; Nazzareno Galiè; Rajeev Malhotra; Stephanie Saxer; Ekkehard Grünig; Benjamin Egenlauf; Ralf Ewert; Alexander Heine; Ryan J Tedford; Brian A Houston; Krzysztof Kasperowicz; Marcin Kurzyna; Stephan Rosenkranz; Simon Herkenrath; Joan Albert Barbera; Isabel Blanco; Rudolf K F Oliveira; Mads Andersen; Laurent Savale; David Systrom; Bradley A Maron; Khodr Tello; Robin Condliffe; Susanna Mak; Claudia Baratto; Steven Hsu; Michele D'Alto; Colm McCabe; Philippe Herve; Horst Olschewski; PEX-NET (Pulmonary Hemodynamics during Exercise Network) ERS-Clinical Research Collaboration

doi:10.1183/13993003.00698-2024

Prognostic relevance of Exercise Pulmonary Hypertension: Results of the multi-center PEX-NET Clinical Research Collaboration

Eur Respir J. 2024 Nov 27:2400698. doi: 10.1183/13993003.00698-2024. Online ahead of print.

Authors

Gabor Kovacs^{1

2}, Marc Humbert³, Alexander Avian⁴, Gregory D Lewis⁵, Silvia Ulrich⁶, Anton Vonk Noordegraaf⁷, Rogerio Souza⁸, Nazzareno Galiè⁹, Rajeev Malhotra⁵, Stephanie Saxer⁶, Ekkehard Grünig¹⁰, Benjamin Egenlauf¹⁰, Ralf Ewert¹¹, Alexander Heine¹¹, Ryan J Tedford¹², Brian A Houston¹², Krzysztof Kasperowicz¹³, Marcin Kurzyna¹³, Stephan Rosenkranz¹⁴, Simon Herkenrath¹⁴, Joan Albert Barbera¹⁵, Isabel Blanco¹⁵, Rudolf K F Oliveira¹⁶, Mads Andersen¹⁷, Laurent Savale³, David Systrom¹⁸, Bradley A Maron^{19

20}, Khodr Tello²¹, Robin Condliffe²², Susanna Mak²³, Claudia Baratto²⁴, Steven Hsu²⁵, Michele D'Alto²⁶, Colm McCabe^{27

28}, Philippe Herve³, Horst Olschewski^{29

2}; PEX-NET (Pulmonary Hemodynamics during Exercise Network) ERS-Clinical Research Collaboration

Affiliations

¹ Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria gabor.kovacs@uniklinikum.kages.at.
² Ludwig Boltzmann Institute for Lung Vascular Research Graz, Graz, Austria.
³ Université Paris-Saclay, Inserm UMR_S 999, Publique Hôpitaux de Paris, Service de Pneumologie et Soins Intensifs Respiratoires, ERN-LUNG, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
⁴ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
⁵ Massachusetts General Hospital, Harvard Medical School, Boston, USA.
⁶ University of Zurich, Zurich, Switzerland.
⁷ Amsterdam University Medical Center, Amsterdam, The Netherlands.
⁸ University of Sao Paulo Medical School, Sao Paulo, Brazil.
⁹ University of Bologna, Bologna, Italy.
¹⁰ University of Heidelberg, Heidelberg, Germany.
¹¹ Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
¹² Medical University of South Carolina, Charlestown, USA.
¹³ Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Otwock, Poland.
¹⁴ University of Cologne, Cologne, Germany.
¹⁵ Department of Pulmonary Medicine, Hospital Clinic-IDIBAPS, University of Barcelona; Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Barcelona, Spain.
¹⁶ Federal University of São Paulo, UNIFESP, São Paulo, Brazil.
¹⁷ Aarhus University, Aarhus, Denmark.
¹⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
¹⁹ Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
²⁰ The University of Maryland-Institute for Health Computing, Bethesda, MD, USA.
²¹ Justus-Liebig-University, Giessen, Germany.
²² University of Sheffield, Sheffield, UK.
²³ Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
²⁴ Department of Cardiology, Ospedale San Luca, IRCCS Istituto Auxologico Italiano, Milan, Italy.
²⁵ Johns Hopkins University School of Medicine, Baltimore, USA.
²⁶ Second University of Naples - Monaldi Hospital, Naples, Italy.
²⁷ Royal Brompton Hospital, London, UK.
²⁸ Imperial College, London, UK.
²⁹ Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

PMID: 39603672
DOI: 10.1183/13993003.00698-2024

Abstract

Background: Exercise pulmonary hypertension (exercise PH) was defined by a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope >3 mmHg·L^-1·min^-1 between rest and exercise in the 2022 ESC/ERS PH guidelines. However, large, multi-center studies on the prognostic relevance of exercise hemodynamics and its added value to resting hemodynamics are missing.

Patients and methods: The PEX-NET (Pulmonary Hemodynamics during Exercise Network) registry enrolled patients who underwent clinically indicated right heart catheterizations both at rest and ergometer exercise from 23 PH-centers worldwide. In this retrospective analysis we included subjects with resting mPAP<25 mmHg and complete hemodynamic data at rest and exercise in the same body position. Mixed effects Cox proportional hazard models with random effect center were applied to identify independent markers of prognosis among the hemodynamic parameters.

Results: We included n=764 patients (64% females, age: 59yrs (IQR:46-69), mPAP: 17 mmHg (IQR:14-20)). Median observation time was 6.8yrs (range:0.1-15.9) and 87 patients (11%) died during follow-up. After adjustment for age, sex, hemoglobin level, and resting hemodynamics, CO (p=0.001; HR: 0.85 (95%CI:0.77-0.93)) and trans-pulmonary gradient (p=0.044; HR: 1.04 (95%CI:1.00-1.08)) at peak exercise and the mPAP/CO slope (p<0.001; HR: 1.12 (95%CI:1.06-1.18)) were the only independent predictors of prognosis. Patients with mPAP/CO slope >3 mmHg·L^-1·min^-1 had significantly worse survival compared to those with ≤3 mmHg·L^-1·min^-1 (p=0.013; HR: 2.04 (95%CI:1.16-3.58)).

Conclusion: The mPAP/CO slope is a robust and independent predictor of prognosis in patients with normal or mildly elevated resting pulmonary arterial pressure that provides prognostic information beyond resting hemodynamics and appears suitable to define exercise PH.